The present invention provides methods of treating cancer of the liver, ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, or renal cell carcinoma that comprise administering to a patient having cancer of the liver, ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, or renal cell carcinoma a therapeutically effective amount of an estrogen agonist/antagonist. The present invention also provides kits for treating cancer of the liver, ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, or renal cell carcinoma that comprises a pharmaceutical composition comprising an estrogen agonist/antagonist and instructions for administering the pharmaceutical composition to treat cancer of the liver, ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, or renal cell carcinoma.
Cancer is still one of the most dreaded diseases, and much effort and money has been spent trying to discover ways to treat cancer. The present invention provides methods of treating certain cancers, namely cancer of the liver, ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, or renal cell carcinoma.
There are two main types of cancer of the liver. The first type is the result of metastasis of cancer from another area in the body. In this type of liver cancer, a cancer cell from another part of the body migrates to the liver and begins growth and tumor formation there. Commonly, the cancer cells that metastasize to the liver come from cancer in the lungs, breast, colon, pancreas or stomach.
The second general type of liver cancer has been called primary liver cancer. This type is composed of subtypes of cancers such as hepatocelluar carcinoma, which is the most common type of liver cancer, fibrolamellar carcinoma, cholangiocarcinoma, hepatoblastoma and angiosarcoma.
Ovarvian cancer is the second most commonly diagnosed and most deadly gynecologic malignancy. Ovarian cancer affects predominantly perimenopausal and postmenopausal women.
Desmoid tumors, also called aggressive fibromatosis, are dense connective tissue tumors.
Glioma is a type of brain tumor, which accounts for 45% of intracranial tumors.
Pancreatic cancer has several varieties including ductal adenocarcinoma, cystadenocarcinoma, intraductal papillary-mucinous tumors, insulinoma, Zollinger-Ellison Syndrome (also known as gastrinoma), vipoma and glucagonoma.
Renal cell carcinoma accounts for about two percent of cancers.
The cancers listed above can all be treated by administering to a patient suffering therefrom a therapeutically effective amount of an estrogen agonist/antagonist.
The use of tamoxifen to treat ovarian cancer, heptaocellular carcinoma, desmoid tumors, malignant gliomas, carcinoma of the pancreas and melanoma is discussed in Gelman, Edward P., Tamoxifen for the Treatment of Malignancies Other Than Breast and Endometrial Carcinoma, Seminars in Oncology, Vol. 24, No. 1, Suppl I (February), 1997, pp SI-65-SI 70.
The present invention provides methods of treating cancer of the liver, ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, or renal cell carcinoma, the methods comprising the step of administering to a patient having cancer of the liver, ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, or renal cell carcinoma a therapeutically effective amount of an estrogen agonist/antagonist.
In a preferred embodiment of the methods, the estrogen agonist/antagonist is a compound of formula (I): 
wherein:
A is selected from CH2 and NR;
B, D and E are independently selected from CH and N;
Y is
(a) phenyl, optionally substituted with 1-3 substituents independently selected from R4;
(b) naphthyl, optionally substituted with 1-3 substituents independently selected from R4;
(c) C3-C8 cycloalkyl, optionally substituted with 1-2 substituents independently selected from R4;
(d) C3-C8 cycloalkenyl, optionally substituted with 1-2 substituents independently selected from R4;
(e) a five membered heterocycle containing up to two heteroatoms selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94 and xe2x80x94S(O)nxe2x80x94, optionally substituted with 1-3 substituents independently selected from R4;
(f) a six membered heterocycle containing up to two heteroatoms selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94 and xe2x80x94S(O)nxe2x80x94 optionally substituted with 1-3 substituents independently selected from R4; or
(g) a bicyclic ring system consisting of a five or six membered heterocyclic ring fused to a phenyl ring, said heterocyclic ring containing up to two heteroatoms selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94 and xe2x80x94S(O)nxe2x80x94, optionally substituted with 1-3 substituents independently selected from R4;
Z1 is
(a) xe2x80x94(CH2)p W(CH2)qxe2x80x94;
(b) xe2x80x94O(CH2)p CR5R6xe2x80x94;
(c) xe2x80x94O(CH2)pW(CH2)qxe2x80x94;
(d) xe2x80x94OCHR2CHR3xe2x80x94; or
(e) xe2x80x94SCHR2CHR3xe2x80x94;
G is
(a) xe2x80x94NR7R8; 
wherein n is 0, 1 or 2; m is 1, 2 or 3; Z2 is xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94CH2xe2x80x94; optionally fused on adjacent carbon atoms with one or two phenyl rings and, optionally independently substituted on carbon with one to three substituents and, optionally, independently on nitrogen with a chemically suitable substituent selected from R4; or
(c) a bicyclic amine containing five to twelve carbon atoms, either bridged or fused and optionally substituted with 1-3 substituents independently selected from R4; or
Z1 and G in combination may be 
W is
(a) xe2x80x94CH2xe2x80x94;
(b) xe2x80x94CHxe2x95x90CHxe2x80x94;
(c) xe2x80x94Oxe2x80x94;
(d) xe2x80x94NR2xe2x80x94;
(e) xe2x80x94S(O)nxe2x80x94; 
(g) xe2x80x94CR2(OH)xe2x80x94;
(h) xe2x80x94CONR2xe2x80x94;
(i) xe2x80x94NR2COxe2x80x94; 
(k) xe2x80x94Cxe2x89xa1Cxe2x80x94;
R is hydrogen or C1-C6 alkyl;
R2 and R3 are independently
(a) hydrogen; or
(b) C1-C4 alkyl;
R4 is
(a) hydrogen;
(b) halogen;
(c) C1-C6 alkyl;
(d) C1-C4 alkoxy;
(e) C1-C4 acyloxy;
(f) C1-C4 alkylthio;
(g) C1-C4 alkylsulfinyl;
(h) C1-C4 alkylsulfonyl;
(i) hydroxy (C1-C4)alkyl;
(j) aryl (C1-C4)alkyl;
(k) xe2x80x94CO2H;
(l) xe2x80x94CN;
(m) xe2x80x94CONHOR;
(n) xe2x80x94SO2NHR;
(o)xe2x80x94NH2;
(p) C1-C4 alkylamino;
(q) C1-C4 dialkylamino;
(r) xe2x80x94NHSO2R;
(s) xe2x80x94NO2;
(t) -aryl; or
(u) xe2x80x94OH;
R5 and R6 are independently C1-C8 alkyl or together form a C3-C10 carbocyclic ring;
R7 and R8 are independently
(a) phenyl;
(b) a C3-C10 carbocyclic ring, saturated or unsaturated;
(c) a C3-C10 heterocyclic ring containing up to two heteroatoms, selected from xe2x80x94Oxe2x80x94, xe2x80x94Nxe2x80x94 and xe2x80x94Sxe2x80x94;
(d) H;
(e) C1-C6 alkyl; or
(f) form a 3 to 8 membered nitrogen containing ring with R5 or R6;
R7 and R8 in either linear or ring form may optionally be substituted with up to three substituents independently selected from C1-C6 alkyl, halogen, alkoxy, hydroxy and carboxy;
a ring formed by R7 and R8 may be optionally fused to a phenyl ring;
e is 0, 1 or 2;
m is 1, 2 or 3;
n is 0, 1 or 2;
p is 0, 1, 2 or 3;
q is 0, 1, 2 or 3;
or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.
In another preferred embodiment of the methods, the estrogen agonist/antagonist is a compound of formula (IA) 
wherein G is 
R4 is H, OH, F, or Cl; and B and E are independently selected from CH and N or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
In another preferred embodiment of the methods, the estrogen agonist/antagonist is (xe2x88x92)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomer thereof; a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
In another preferred embodiment of the methods, the estrogen agonist/antagonist is (xe2x88x92)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol, D-tartrate salt.
In another preferred embodiment of the methods, the estrogen agonist/antagonist is 4-hydroxy tamoxifen, droloxifene, toremifene, centchroman, idoxifene, raloxifene, 6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol, {4-[2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benxo[b]thiophen-3-yl]-methanone, EM-652, EM-800, GW 5638, GW 7604, or an optical or geometric isomer thereof; pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or prodrug thereof.
In another preferred embodiment of the methods, the estrogen agonist/antagonist is a compound of formula V or VI: 
wherein:
R1B is selected from H, OH, xe2x80x94Oxe2x80x94C(O)xe2x80x94C1-C12 alkyl (straight chain or branched), xe2x80x94Oxe2x80x94C1-C12 alkyl (straight chain or branched or cyclic), or halogens or C1-C4 halogenated ethers;
R2B, R3B, R4B, R5B, and R6B are independently selected from H, OH, xe2x80x94Oxe2x80x94C(O)xe2x80x94C1-C12 (straight chain or branched), xe2x80x94Oxe2x80x94C1-C12 (straight chain or branched or cyclic), halogens, or C1-C4 halogenated ethers, cyano, C1-C6 alkyl (straight chain or branched), or trifluoromethyl;
XA is selected from H, C1-C6 alkyl, cyano, nitro, trifluoromethyl, and halogen;
s is 2 or 3;
YA is the moiety: 
wherein:
a) R7B and R8B are independently selected from the group of H, C1-C6 alkyl, or phenyl optionally substituted by CN, C1-C6 alkyl (straight chain or branched), C1-C6 alkoxy (straight chain or branched), halogen, xe2x80x94OH, xe2x80x94CF3, or xe2x80x94OCF3; or
b) R7B and R8B are concatenated to form a five-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, xe2x80x94CO2H, xe2x80x94CN, xe2x80x94CONHR1B, xe2x80x94NH2, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)2, xe2x80x94NHSO2R1B, xe2x80x94NHCOR1B, xe2x80x94NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl; or
c) R7B and R8B are concatenated to form a six-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, xe2x80x94CO2H, xe2x80x94CN, xe2x80x94CONHR1B, xe2x80x94NH2, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)2, xe2x80x94NHSO2R1B, xe2x80x94NHCOR1B, xe2x80x94NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl; or
d) R7B and R8B are concatenated to form a seven-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, xe2x80x94CO2H, xe2x80x94CN, xe2x80x94CONHR1B, xe2x80x94NH2, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)2, xe2x80x94NHSO2R1B, xe2x80x94NHCOR1B, xe2x80x94NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl; or
e) R7B and R8B are concatenated to form an eight-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, xe2x80x94CO2H, xe2x80x94CN, xe2x80x94CONHR1B, xe2x80x94NH2, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C4alkyl)2, xe2x80x94NHSO2R1B, xe2x80x94NHCOR1B, xe2x80x94NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl; or
f) R7B and R8B are concatenated to form a saturated bicyclic heterocycle containing from 6-12 carbon atoms either bridged or fused and containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, xe2x80x94CO2H, xe2x80x94CN, xe2x80x94CONHR1B, xe2x80x94NH2, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)2, xe2x80x94NHSO2R1B, xe2x80x94NHCOR1B, xe2x80x94NO2, or phenyl optionally substituted with 1-3 (C1-C4) alkyl; or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.
In another preferred embodiment of the methods, the estrogen agonist/antagonist is the compound of formula Va: 
or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.
In another preferred embodiment of the methods, the estrogen agonist/antagonist is the compound of formula III (EM-652) or formula IV (EM-800) below: 
or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.
Also provided by the present invention are kits for use by a consumer to treat cancer of the liver, ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, or renal cell carcinoma, the kits comprising:
(a) a pharmaceutical composition comprising an estrogen agonist/antagonist; and
(b) instructions describing a method of using the pharmaceutical composition to treat cancer of the liver, ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, or renal cell carcinoma.
In a preferred embodiment of the kits, the estrogen agonist/antagonist is a compound of formula (I): 
wherein:
A is selected from CH2 and NR;
B, D and E are independently selected from CH and N;
Y is
(a) phenyl, optionally substituted with 1-3 substituents independently selected from R4;
(b) naphthyl, optionally substituted with 1-3 substituents independently selected from R4;
(c) C3-C8 cycloalkyl, optionally substituted with 1-2 substituents independently selected from R4;
(d) C3-C8 cycloalkenyl, optionally substituted with 1-2 substituents independently selected from R4;
(e) a five membered heterocycle containing up to two heteroatoms selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94 and xe2x80x94S(O)nxe2x80x94, optionally substituted with 1-3 substituents independently selected from R4;
(f) a six membered heterocycle containing up to two heteroatoms selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94 and xe2x80x94S(O)nxe2x80x94 optionally substituted with 1-3 substituents independently selected from R4; or
(g) a bicyclic ring system consisting of a five or six membered heterocyclic ring fused to a phenyl ring, said heterocyclic ring containing up to two heteroatoms selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94 and xe2x80x94S(O)nxe2x80x94, optionally substituted with 1-3 substituents independently selected from R4;
Z1 is
(a) xe2x80x94(CH2)p W(CH2)qxe2x80x94;
(b) xe2x80x94O(CH2)p CR5R6xe2x80x94;
(c) xe2x80x94O(CH2)pW(CH2)qxe2x80x94;
(d) xe2x80x94OCHR2CHR3xe2x80x94; or
(e) xe2x80x94SCHR2CHR3xe2x80x94;
G is
(a) xe2x80x94NR7R8; 
wherein n is 0, 1 or 2; m is 1, 2 or 3; Z2 is xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94CH2xe2x80x94; optionally fused on adjacent carbon atoms with one or two phenyl rings and, optionally independently substituted on carbon with one to three substituents and, optionally, independently on nitrogen with a chemically suitable substituent selected from R4; or
(c) a bicyclic amine containing five to twelve carbon atoms, either bridged or fused and optionally substituted with 1-3 substituents independently selected from R4; or
Z1 and G in combination may be 
W is
(a) xe2x80x94CH2xe2x80x94;
(b) xe2x80x94CHxe2x95x90CHxe2x80x94;
(c) xe2x80x94Oxe2x80x94;
(d) xe2x80x94NR2xe2x80x94;
(e) xe2x80x94S(O)nxe2x80x94; 
(g) xe2x80x94CR2(OH)xe2x80x94;
(h) xe2x80x94CONR2xe2x80x94;
(i) xe2x80x94NR2COxe2x80x94; 
(k) xe2x80x94Cxe2x89xa1Cxe2x80x94;
R is hydrogen or C1-C6 alkyl;
R2 and R3 are independently
(a) hydrogen; or
(b) C1-C4 alkyl;
R4 is
(a) hydrogen;
(b) halogen;
(c) C1-C6 alkyl;
(d) C1-C4alkoxy;
(e) C1-C4 acyloxy;
(f) C1-C4 alkylthio;
(g) C1-C4 alkylsulfinyl;
(h) C1-C4 alkylsulfonyl;
(i) hydroxy (C1-C4)alkyl;
(j) aryl (C1-C4)alkyl;
(k) xe2x80x94CO2H;
(l) xe2x80x94CN;
(m) xe2x80x94CONHOR;
(n) xe2x80x94SO2NHR;
(o)xe2x80x94NH2;
(p) C1-C4 alkylamino;
(q) C1-C4 dialkylamino;
(r) xe2x80x94NHSO2R;
(s) xe2x80x94NO2;
(t) -aryl; or
(u) xe2x80x94OH;
R5 and R6 are independently C1-C8 alkyl or together form a C3-C10 carbocyclic ring;
R7 and R8 are independently
(a) phenyl;
(b) a C3-C10 carbocyclic ring, saturated or unsaturated;
(c) a C3-C10 heterocyclic ring containing up to two heteroatoms, selected from xe2x80x94Oxe2x80x94, xe2x80x94Nxe2x80x94 and xe2x80x94Sxe2x80x94;
(d) H;
(e) C1-C6 alkyl; or
(f) form a 3 to 8 membered nitrogen containing ring with R5 or R6;
R7 and R8 in either linear or ring form may optionally be substituted with up to three substituents independently selected from C1-C6 alkyl, halogen, alkoxy, hydroxy and carboxy;
a ring formed by R7 and R8 may be optionally fused to a phenyl ring;
e is 0, 1 or 2;
m is 1, 2 or 3;
n is 0, 1 or 2;
p is 0, 1, 2 or 3;
q is 0, 1, 2 or 3;
or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.
In another preferred embodiment of the kits, the estrogen agonist/antagonist is a compound of formula (IA): 
wherein G is 
R4 is H, OH, F, or Cl; and B and E are independently selected from CH and N or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
In another preferred embodiment of the kits, the estrogen agonist/antagonist is (xe2x88x92)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
In another preferred embodiment of the kits, the estrogen agonist/antagonist is (xe2x88x92)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol, D-tartrate salt.
In another preferred embodiment of the kits, the estrogen agonist/antagonist is 4-hydroxy tamoxifen, droloxifene, toremifene, centchroman, idoxifene, raloxifene, 6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol, {4-[2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzol[b]thiophen-3-yl]-methanone, EM-652, EM-800, GW 5638, GW 7604, or an optical or geometric isomer thereof; pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or prodrug thereof.
In another preferred embodiment of the kits, the estrogen agonist/antagonist is a compound of formula V or VI: 
wherein:
R1B is selected from H, OH, xe2x80x94Oxe2x80x94C(O)xe2x80x94C1-C12 alkyl (straight chain or branched), xe2x80x94Oxe2x80x94C1-C12 alkyl (straight chain or branched or cyclic), or halogens or C1-C4 halogenated ethers;
R2B, R3B, R4B, R5B, and R6B are independently selected from H, OH, xe2x80x94Oxe2x80x94C(O)xe2x80x94C1-C12 (straight chain or branched), xe2x80x94Oxe2x80x94C1-C12 (straight chain or branched or cyclic), halogens, or C1-C4 halogenated ethers, cyano, C1-C6 alkyl (straight chain or branched), or trifluoromethyl;
XA is selected from H, C1-C6 alkyl, cyano, nitro, trifluoromethyl, and halogen;
s is 2 or 3;
YA is the moiety: 
wherein:
a) R7B and R8B are independently selected from the group of H, C1-C6 alkyl, or phenyl optionally substituted by CN, C1-C6 alkyl (straight chain or branched), C1-C6 alkoxy (straight chain or branched), halogen, xe2x80x94OH, xe2x80x94CF3, or xe2x80x94OCF3; or
b) R7B and R8B are concatenated to form a five-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, xe2x80x94CO2H, xe2x80x94CN, xe2x80x94CONHR1B, xe2x80x94NH2, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)2, xe2x80x94NHSO2R1B, xe2x80x94NHCOR1B, xe2x80x94NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl; or
c) R7B and R8B are concatenated to form a six-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, xe2x80x94CO2H, xe2x80x94CN, xe2x80x94CONHR1B, xe2x80x94NH2, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)2, xe2x80x94NHSO2R1B, xe2x80x94NHCOR1B, xe2x80x94NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl; or
d) R7B and R8B are concatenated to form a seven-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, xe2x80x94CO2H, xe2x80x94CN, xe2x80x94CONHR1B, xe2x80x94NH2, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)2, xe2x80x94NHSO2R1B, xe2x80x94NHCOR1B, xe2x80x94NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl; or
e) R7B and R8B are concatenated to form an eight-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, xe2x80x94CO2H, xe2x80x94CN, xe2x80x94CONHR1B, xe2x80x94NH2, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)2, xe2x80x94NHSO2R1B, xe2x80x94NHCOR1B, xe2x80x94NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl; or
f) R7B and R8B are concatenated to form a saturated bicyclic heterocycle containing from 6-12 carbon atoms either bridged or fused and containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, xe2x80x94CO2H, xe2x80x94CN, xe2x80x94CONHR1B, xe2x80x94NH2, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)2, xe2x80x94NHSO2R1B, xe2x80x94NHCOR1B, xe2x80x94NO2, or phenyl optionally substituted with 1-3 (C1-C4) alkyl; or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.
In another preferred embodiment of the kits, the estrogen agonist/antagonist is the compound of formula Va (TSE-424) below: 
or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.
In another preferred embodiment of the kits, the estrogen agonist/antagonist is the compound of formula III (EM-652) or formula IV (EM-800) below: 
or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.
In another preferred embodiment of the kits, the kits further comprise an additional compound that is useful to treat cancer of the liver, ovarian cancer, a desmoid tumor, glioma, pancreatic cancer, or renal cell carcinoma.